Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Increases in leukostasis/monocyte adhesion to the capillary endothelium (leukostasis) and decreases in retinal blood flow may be causally associated and are implicated in the pathogenesis of diabetic retinopathy. In this study, we demonstrate that increases in leukostasis are observed in insulin-resistant states without diabetes, whereas decreases in retinal blood flow require diabetes and hyperglycemia. Microimpaction studies using beads mimicking retinal capillary obstruction by leukocytes did not affect retinal blood flow. In diabetic rats, treatment with the antioxidant alpha-lipoic acid normalized the amount of leukostasis but not retinal blood flow. In contrast, treatment with D-alpha-tocopherol and protein kinase-C beta-isoform inhibition (LY333531) prevented the increases in leukostasis and decreases in retinal blood flow in diabetic rats. Serum hydroxyperoxide, a marker of oxidative stress, was increased in diabetic rats, but normalized by treatment with antioxidants alpha-lipoic acid and D-alpha-tocopherol and, surprisingly, PKC beta-isoform inhibition. These findings suggest that leukostasis is associated with endothelial dysfunction, insulin resistance, and oxidative stress but is not related to retinal blood flow and is not sufficient to cause diabetic-like retinopathy. Moreover, treatment with PKC beta inhibition is effective to normalize diabetes or hyperglycemia-induced PKC beta-isoform activation and oxidative stress.
...
PMID:Characterization of retinal leukostasis and hemodynamics in insulin resistance and diabetes: role of oxidants and protein kinase-C activation. 1260 27

Several interacting and mutually perpetuating biochemical pathways or systems, such as the polyol pathway, nonenzymatic glycation, oxidative stress, protein kinase Cbeta and the reninangiotensin system, may be activated as a result of sustained hyperglycemia in diabetes. These abnormally activated pathways may in turn influence several vasoactive factors and cytokines, such as vascular endothelial growth factor, interleukin-6, pigment epithelium-derived factor and endostatin, which are important in mediating the functional and structural changes of diabetic retinopathy. Intricate and interacting regulatory mechanisms involving these factors may control their ultimate ability to produce biologically significant effects. A better understanding of these factors and their interactions may assist in the development of adjuvant therapies for the treatment of diabetic retinopathy. (c) 2002 Prous Science. All rights reserved.
...
PMID:Pathophysiology of Diabetic Retinopathy. 1267 48

Evidence implicates hyperglycemia-derived oxygen free radicals as mediators of diabetic complications. However, intervention studies with classic antioxidants, such as vitamin E, failed to demonstrate any beneficial effect. Recent studies demonstrate that a single hyperglycemia-induced process of overproduction of superoxide by the mitochondrial electron-transport chain seems to be the first and key event in the activation of all other pathways involved in the pathogenesis of diabetic complications. These include increased polyol pathway flux, increased advanced glycosylation end product formation, activation of protein kinase C, and increased hexosamine pathway flux. Superoxide overproduction is accompanied by increased nitric oxide generation, due to an endothelial NOS and inducible NOS uncoupled state, a phenomenon favoring the formation of the strong oxidant peroxynitrite, which in turn damages DNA. DNA damage is an obligatory stimulus for the activation of the nuclear enzyme poly(ADP-ribose) polymerase. Poly(ADP-ribose) polymerase activation in turn depletes the intracellular concentration of its substrate NAD(+), slowing the rate of glycolysis, electron transport, and ATP formation, and produces an ADP-ribosylation of the GAPDH. These processes result in acute endothelial dysfunction in diabetic blood vessels that, convincingly, also contributes to the development of diabetic complications. These new findings may explain why classic antioxidants, such as vitamin E, which work by scavenging already-formed toxic oxidation products, have failed to show beneficial effects on diabetic complications and may suggest new and attractive "causal" antioxidant therapy. New low-molecular mass compounds that act as SOD or catalase mimetics or L-propionyl-carnitine and lipoic acid, which work as intracellular superoxide scavengers, improving mitochondrial function and reducing DNA damage, may be good candidates for such a strategy, and preliminary studies support this hypothesis. This "causal" therapy would also be associated with other promising tools such as LY 333531, PJ34, and FP15, which block the protein kinase beta isoform, poly(ADP-ribose) polymerase, and peroxynitrite, respectively. While waiting for these focused tools, we may have other options: thiazolinediones, statins, ACE inhibitors, and angiotensin 1 inhibitors can reduce intracellular oxidative stress generation, and it has been suggested that many of their beneficial effects, even in diabetic patients, are due to this property.
...
PMID:New insights on oxidative stress and diabetic complications may lead to a "causal" antioxidant therapy. 1271 23

In type 2 diabetes, insulin activation of muscle glycogen synthase (GS) is impaired. This defect plays a major role for the development of insulin resistance and hyperglycemia. In animal muscle, insulin activates GS by reducing phosphorylation at both NH(2)- and COOH-terminal sites, but the mechanism involved in human muscle and the defect in type 2 diabetes remain unclear. We studied the effect of insulin at physiological concentrations on glucose metabolism, insulin signaling and phosphorylation of GS in skeletal muscle from type 2 diabetic and well-matched control subjects during euglycemic-hyperinsulinemic clamps. Analysis using phospho-specific antibodies revealed that insulin decreases phosphorylation of sites 3a + 3b in human muscle, and this was accompanied by activation of Akt and inhibition of glycogen synthase kinase-3alpha. In type 2 diabetic subjects these effects of insulin were fully intact. Despite that, insulin-mediated glucose disposal and storage were reduced and activation of GS was virtually absent in type 2 diabetic subjects. Insulin did not decrease phosphorylation of sites 2 + 2a in healthy human muscle, whereas in diabetic muscle insulin infusion in fact caused a marked increase in the phosphorylation of sites 2 + 2a. This phosphorylation abnormality likely caused the impaired GS activation and glucose storage, thereby contributing to skeletal muscle insulin resistance, and may therefore play a pathophysiological role in type 2 diabetes.
...
PMID:Increased phosphorylation of skeletal muscle glycogen synthase at NH2-terminal sites during physiological hyperinsulinemia in type 2 diabetes. 1276 49

Increased leukocyte-endothelial cell adhesion is a key early event in the development of retinopathy and atherogenesis in diabetic patients. We recently reported that raised activity of glycosylating enzyme [beta]1,6 acetylglucosaminyltransferase (core 2 GlcNAc-T) is responsible for increased leukocyte-endothelial cell adhesion and capillary occlusion in retinopathy. Here, we demonstrate that elevated glucose increases the activity of core 2 GlcNAc-T and adhesion of human leukocytes to retinal capillary endothelial cells, in a dose-dependent manner, through diabetes-activated serine/threonine protein kinase C beta2 (PKCbeta2)-dependent phosphorylation. This regulatory mechanism, involving phosphorylation of core 2 GlcNAc-T, is also present in polymorphonuclear leukocytes isolated from type 1 and type 2 diabetic patients. Inhibition of PKCbeta2 activation with the specific inhibitor, LY379196, attenuated serine phosphorylation of core 2 GlcNAc-T and prevented increased leukocyte-endothelial cell adhesion. Raised activity of core 2 GlcNAc-T was associated with a threefold increase in O-linked glycosylation of P-selectin glycoprotein ligand-1 on the surface of leukocytes of diabetic patients compared with age-matched control subjects. PKCbeta2-dependent phosphorylation of core 2 GlcNAc-T may thus represent a novel regulatory mechanism for activation of this key enzyme in mediating increased leukocyte-endothelial cell adhesion and capillary occlusion in diabetic retinopathy.
...
PMID:Protein kinase C beta2-dependent phosphorylation of core 2 GlcNAc-T promotes leukocyte-endothelial cell adhesion: a mechanism underlying capillary occlusion in diabetic retinopathy. 1276 65

Abnormalities in the cell cycle are responsible for the majority of human neoplasias. Most abnormalities occur due to hyperphosphorylation of the tumor suppressor gene Rb by the key regulators of the cell cycle, the cyclin-dependent kinases (CDKs). Thus, a pharmacological CDK inhibitor may be useful in the prevention and/or treatment of human neoplasms. Flavopiridol is a flavonoid with interesting preclinical properties: (1) potent CDK inhibitory activity; (2) it depletes cyclin D1 and vascular endothelial growth factor mRNA by transcriptional and posttranscriptional mechanisms, respectively; (3) it inhibits positive elongation factor B, leading to transcription "halt"; and (4) it induces apoptosis in several preclinical models. The first phase I trial of a CDK inhibitor, flavopiridol, has been completed. Dose-limiting toxicities included secretory diarrhea and proinflammatory syndrome. Antitumor activity was observed in some patients with non-Hodgkin's lymphoma and renal, colon, and prostate cancers. Concentrations between 300 and 500 n M-necessary to inhibit CDK-were achieved safely. Phase II trials with infusional flavopiridol and phase I infusional trials in combination with standard chemotherapy are being completed with encouraging results. A novel phase I trial of 1-h flavopiridol administration was recently completed. The maximum tolerated doses using flavopiridol daily for 5, 3, and 1 consecutive days are 37.5, 50, and 62.5 mg/m(2) per day. Dose-limiting toxicities include vomiting, neutropenia, proinflammatory syndrome, and diarrhea. Plasma flavopiridol concentrations achieved were in the range 1.5-3.5 MICRO M. Phase II/III trials using this 1-h schedule in several tumor types including non-small-cell lung cancer, chronic lymphocytic leukemia, mantle cell lymphoma, and head and neck cancer are being conducted worldwide. UCN-01, the second CDK modulator that has entered clinical trials, has unique preclinical properties: (1) it inhibits protein kinase C (PKC) activity; (2) it promotes cell-cycle arrest by accumulation in p21/p27; (3) it induces apoptosis in several preclinical models; and (4) it abrogates the G(2) checkpoint by inhibition of chk1. The last of these represents a novel strategy to combine UCN-01 with DNA-damaging agents. In the initial UCN-01 clinical trial (continuous infusion for 72 h), a prolonged half-life of about 600 h (100 times longer than in preclinical models) was observed. The maximum tolerated dose was 42.5 mg/m(2) per day for 3 days. Dose-limiting toxicities were nausea/vomiting, hypoxemia, and symptomatic hyperglycemia. One patient with melanoma achieved a partial response (8 months). Another patient with refractory anaplastic large-cell lymphoma had no evidence of disease at >4 years. Bone marrow and tumor samples obtained from some patients revealed loss in adducin phosphorylation, a substrate of PKC. Phase I trials with shorter infusions are being completed. In summary, the first two CDK modulators have shown encouraging results in early clinical trials. A question that remains unanswered is "Which is the best schedule for combination with standard antitumor agents?" Moreover, it is still unclear which pharmacodynamic endpoint reflects loss of CDK activity in tissue samples from patients in these trials. Despite these caveats, we feel that CDKs are sensible targets for cancer therapy and that there are several small-molecule CDK modulators in clinical trials with encouraging results.
...
PMID:Novel direct and indirect cyclin-dependent kinase modulators for the prevention and treatment of human neoplasms. 1281 36

Hyperglycemia is a crucial factor in the development of diabetic nephropathy. We previously showed that high glucose upregulates thrombospondin 1 (TSP1)-dependent transforming growth factor (TGF)-beta activation by altering cGMP-dependent protein kinase (PKG) activity as a result of decreased nitric oxide signaling. In the present study, we showed that high glucose concentrations significantly reduced endogenous PKG activity. To further examine the mechanisms by which PKG regulates TSP1 expression and TSP1-dependent TGF-beta activation, we generated stably transfected rat mesangial cells (RMCs) with inducible expression tetracycline-induced gene expression of the catalytic domain of PKG. After tetracycline induction, the catalytic domain of PKG is expressed as a cGMP-independent active kinase. Expression of the catalytic domain prevented high glucose-mediated increases in transcription of the TSP1 gene with no alteration in TSP1 mRNA stability. Glucose stimulation of TSP1 protein expression and TGF-beta bioactivity were also downregulated. TGF-beta-dependent fibronectin and type IV collagen expression under high glucose conditions were significantly reduced upon catalytic domain expression in transfected RMCs. These results show that constitutively active PKG inhibits the fibrogenic potential of high glucose through repression of TSP1-dependent TGF-beta bioactivity, suggesting that gene transfer of the catalytic domain of PKG might provide a new strategy for treatment of diabetic renal fibrosis.
...
PMID:Expression of constitutively active cGMP-dependent protein kinase prevents glucose stimulation of thrombospondin 1 expression and TGF-beta activity. 1288 34

Diabetes mellitus (DM) causes myocardial remodeling on the subcellular level and alterations in the function of the cell membranes ion transport systems resulting in contractile dysfunction. The present study was aimed to investigate the expression and activation of mitogen-activated protein kinases (MAPKs) and their possible role in the acute diabetic rat hearts. Rats were injected with single dose of streptozotocin (45 mg/kg, i.v.), and after 1 week the disease was manifested by hyperglycemia and cardiac dysfunction. The Langendorff-perfused hearts were subjected to ischemia (5 or 30 min occlusion of LAD coronary artery). The protein pattern in cytosolic fraction of the heart tissue was determined after electrophoretic separation. The levels and activation of MAPKs were determined by Western blot analysis using specific antibodies. No differences between the diabetics and controls in the level of ERKs were found at baseline. However, in DM samples ERKs phosphorylation was markedly increased, and further changes occurred during ischemia. Also content of phoshorylated c-Raf kinase (an upstream activator of ERKs) was slightly increased at baseline conditions in the diabetic samples. In contrast, no significant changes in the contents and phosphorylation of p38-MAPK were observed at baseline. But some differences in the p38-MAPK phosphorylation were found during ischemia. The results show that differential pattern of protein kinase cascades activation in the diabetic hearts might be account for the modulation of their response to ischemia.
...
PMID:Mitogen-activated protein kinases in the acute diabetic myocardium. 1295 99

Hyperglycemia-induced alterations in mesangial (MES) cell function and extracellular matrix (ECM) protein accumulation are seen in diabetic glomerulopathy. Transforming growth factor-beta1 (TGF-beta1) mediates high-glucose-induced matrix production in the kidney. Recent studies demonstrated that some of the effects of high glucose on cellular metabolism are mediated by the hexosamine biosynthesis pathway (HBP) in which fructose-6-phosphate is converted to glucosamine (GlcN) 6-phosphate. We previously showed that the high-glucose-mediated fibronectin and laminin synthesis in MES cells is mediated by the HBP and that GlcN is more potent than glucose in inducing TGF-beta1 promoter luciferase activity. In this study, we investigated the hypothesis that the effects of glucose on MES matrix production occur via hexosamine regulation of TGF-beta1. Culturing simian virus (SV)-40-transformed rat kidney MES cells in 25 mM glucose (HG) for 48 h increases cellular fibronectin and laminin levels about twofold on Western blots compared with low glucose (5 mM). GlcN (1.5 mM) or TGF-beta1 (2.5-5 ng/ml) for 24-48 h also increases ECM synthesis. However, the effects of HG or GlcN with TGF-beta1 are not additive. The presence of anti-TGF-beta1 antibodies (20 microg/ml) blocks both TGF-beta1- and GlcN-induced fibronectin synthesis. TGF-beta1 increased ECM levels via PKA (laminin and fibronectin) and PKC (fibronectin) pathways. Similarly, TGF-beta1 and hexosamines led to nonadditive increases in phosphorylation of the cAMP responsive element binding transcription factor. These results suggest that the effects of excess glucose on MES ECM synthesis occur via HBP-mediated regulation of TGF-beta1.
...
PMID:Hexosamines and TGF-beta1 use similar signaling pathways to mediate matrix protein synthesis in mesangial cells. 1455 14

Hyperglycemia and hypercapnia aggravate intra-ischemic acidosis and subsequent brain damage. However, hyperglycemia causes more extensive post-ischemic damage than hypercapnia, particularly in the cingulate cortex. We investigated the changes in the subcellular distribution of protein kinase Cgamma (PKCgamma) and the Ca2+/calmodulin-dependent protein kinase II (CaMKII), as well as changes in protein tyrosine phosphorylation during and following 10 min normoglycemic, hyperglycemic (plasma glucose approximately 20 mM) and hypercapnic (paCO2) approximately 300 mm Hg) global cerebral ischemia. During reperfusion period, the translocation to cell membranes of PKCgamma, but not CaMKII, was prolonged by intra-ischemic hyperglycemia, while it was only marginally affected by hypercapnia. The tyrosine-phosphorylation of proteins in the synaptosomal membranes, as well as the extracellular signal-regulated kinase (ERK) in the cytosol, markedly increased during reperfusion following hyperglycemic ischemia, but to a lesser degree following hypercapnic ischemia. Our data suggest that PKCgamma, tyrosine kinase and ERK systems are involved in the process of ischemic damage in the cingulate cortex, where hyperglycemia may affect these kinases through an additional mechanism other than exaggerated acidosis.
...
PMID:Hyperglycemia and hypercapnia differently affect post-ischemic changes in protein kinases and protein phosphorylation in the rat cingulate cortex. 1467 11


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---